Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/86—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
  • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
  • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• This invention relates to certain iminobenzoxazines, iminobenzthiazines and iminoquinazolines, their N-oxides, salts and compositions suitable for agronomic and nonagronomic uses, including those uses listed below, and a method of their use for controlling invertebrate pests in both agronomic and nonagronomic environments.
• invertebrate pests The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer.
• the control of invertebrate pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds that are more effective, less costly, less toxic, environmentally safer or have different modes of action.
• ⁇ L 9202078 discloses N-acyl anthranilic acid derivatives of Formula i as insecticides
• X is a direct bond
• Y is H or C j -Cs alkyl
• Z is ⁇ H 2 , NH(C 1 -C 3 alkyl) or N(C 1 -C alkyl) 2
• R 1 through R 9 are independently H, halogen, C j -Cg alkyl, phenyl, hydroxy, C ⁇ -Cg alkoxy or C j -C ⁇ acyloxy.
• WO 00/31082 discloses pyrimidin-4-enamines of Formula ii as fungicides
• A is a fused benzene ring
• R 1 , R 2 and R 3 are H, halogen, optionally substituted alkyl, alkenyl or alkynyl
• R 4 is optionally substituted phenyl
• R 5 is optionally substituted alkyl, alkenyl or alkynyl
• R 6 is H or optionally substituted alkyl, alkenyl or alkynyl.
• This invention pertains to a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula I, its N-oxide or an agriculturally suitable salt of the compound (e.g., as a composition described herein)
• B is O ⁇ or ⁇ R 1 ;
• J is a phenyl ring, a naphthyl ring system, a 5- or 6-membered heteroaromatic ring or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system wherein each ring or ring system is optionally substituted with 1 to 4 R 5 ;
• R 1 is K; each K is independently G; C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -Cg alkynyl, C 3 -C 6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, G, C ⁇ , ⁇ O 2 , hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C 1 -C 4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl,
• R 2 is H or K
• each R 4 is independently a phenyl, benzyl, phenoxy or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted with from one to three substituents independently selected from R 6 ;
• eac R 5 is independently Cj-C 6 alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C 3 -C 6 cycloalkyl, C j -Cg haloalkyl, C 2 -Cg haloalkenyl, C 2 -C6 haloalkynyl, C -C6 halocycloalkyl, halogen, CN, CO 2 H, CONH 2 , NO 2 , hydroxy, C r C 4 alkoxy, C 1
• R 10 is H, C ⁇ -0 alkyl or -C4 haloalkyl
• R 11 is H or C C 4 alkyl; and n is an integer from 1 to 4.
• This invention also relates to such a method wherein the invertebrate pest or its environment is contacted with a biologically effective amount of a compound of Formula I or a composition comprising a compound of Formula I and a biologically effective amount of at least one additional compoundOr agent for controlling invertebrate pests.
• This invention also pertains to a compound of Formula Is, N-oxides or salts thereof
• B is O or S;
• J is a phenyl ring, a naphthyl ring system, a 5- or 6-membered heteroaromatic ring or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system wherein each ring or ring system is optionally substituted with 1 to 4 R 5 ;
• R 2 is H; G; C ⁇ Cg alkyl, C 2 -C6 alkenyl, C 2 -Cg alkynyl, C 3 -Cg cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, G, C ⁇ , ⁇ O , hydroxy, C1-C alkoxy, C1-C4 haloalkoxy,
• C 1 -C4 alkylthio, C1-C4 alkylsulfinyl, C 1 -C alkylsulfonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylcarbonyl, C 3 -Cg trialkylsilyl, or a phenyl, phenoxy or 5- or 6-membered heteroaromatic ring, each ring optionally substituted with one to three substituents independently selected from R 6 ; hydroxy; C1-C4 alkoxy; C1-C4 alkylamino; C 2 -C ⁇ dialkylamino; C 3 -Cg cycloalkylamino; C -Cg alkoxycarbonyl and C 2 -Cg alkylcarbonyl; G is a 5- or 6-membered nonaromatic carbocyclic or heterocyclic ring, optionally including one or two ring members selected from the group consisting of C( O), SO and S(O) 2
• each R 4 is independently a phenyl, benzyl, phenoxy or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted with one to three substituents independently selected from R 6 ;
• eac R 5 is independently C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C
• compositions for controlling an invertebrate pest comprising a biologically effective amount of a compound of Formula I and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
• additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
• compositions optionally further comprising an effective amount of at least one additional biologically active compound or agent.
• alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, t-propyl, t-propyl, or the different butyl, pentyl or hexyl isomers.
• alkenyl includes straight-chain or branched alkenes such as 1-propenyl, 2-propenyl, and the different butenyl, pentenyl andhexenyl isomers.
• Alkenyl also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl.
• Alkynyl includes straight-chain or branched alkynes such as 1 -propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
• Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
• Alkoxy includes, for example, methoxy, ethoxy, 77-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
• Alkoxyalkyl denotes alkoxy substitution on alkyl.
• alkoxyalkyl examples include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
• Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexyl hio isomers.
• Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Trialkylsilyl includes (CH 3 ) 3 Si, (CH 3 CH 2 ) 3 Si and [(CH 3 ) 3 C](CH 3 ) 2 Si.
• (Alkyl)cycloalkylamino means a cycloalkylamino group where the hydrogen atom is replaced by an alkyl radical; examples include groups such as (methyl) cyclopropylamino, (ethyl)cyclobutylamino, (iyo-propyl)cyclopentylamino and (methyl)cyclohexylamino.
• the cycloalkyl in cycloalkylamino and (alkyl)cycloalkylamino is C 3 -Cg cycloalkyl, while the alkyl in (alkyl)cycloalkylamino is C 1 -C 4 alkyl.
• aromatic indicates that each of the ring atoms is essentially in the same plane and has a ?-orbital perpendicular to the ring plane, and in which (4n + 2) ⁇ electrons, when n is 0 or a positive integer, are associated with the ring to comply with H ⁇ ckel's rule.
• aromatic ring system denotes fully unsaturated carbocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic.
• Aromatic carbocyclic ring or fused carbobicyclic ring systems includes fully aromatic carbocycles and carbocycles in which at least one ring of a polycyclic ring system is aromatic (e.g. phenyl and naphthyl).
• nonaromatic carbocyclic ring denotes fully saturated carbocycles as well as partially or fully unsaturated carbocycles where the H ckel rule is not satisfied by the ring.
• hetero in connection with rings or ring systems refers to a ring or ring system in which at least one ring atom is not carbon and which can contain 1 to 4 hetero atoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs.
• heteroring or ring system and “aromatic fused heterobicyclic ring system” includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the H ckel rule is satisfied).
• nonaromatic heterocyclic ring or ring system denotes fully saturated heterocycles as well as partially or fully unsaturated heterocycles where the H ⁇ ckel rule is not satisfied by any of the rings in the ring system.
• the heterocyclic ring or ring system can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
• halogen either alone or in compound words such as “haloalkyl” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
• haloalkynyl examples include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
• haloalkoxy examples include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
• alkylcarbonyl examples include C(O)CH 3 , C(O)CH 2 CH 2 CH 3 and C(O)CH(CH 3 ) 2 .
• the total number of carbon atoms in a substituent group is indicated by the "Cj-Cj" prefix where i and j are numbers from 1 to 8.
• C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl
• C 2 alkoxyalkyl designates CH OCH 2
• C 3 alkoxyalkyl designates, for example, CH 3 CH(OCH 3 ), CH 3 OCH 2 CH 2 or CH 3 CH 2 OCH 2
• C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 and CH CH 2 OCH 2 CH 2 .
• a compound of Formula I comprises a heterocyclic ring, all substituents are attached to this ring through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
• substituents When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1 , said substituents (when they exceed 1) are independently selected from the group of defined substituents. Further, when the subscript indicates a range, e.g. (R)i_ j , then the number of substituents may be selected from the integers between i and j inclusive.
• the ter “optionally substituted” indicates that a moiety may be substituted or unsubstituted.
• the term “optionally substituted with from one to three substituents” and the like indicates that the moiety may be unsubstituted or from one to three of the available positions on the moiety may be substituted.
• R 4 When a moiety contains a substituent which can be hydrogen, for example R 4 , then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said moiety being unsubstituted.
• Compounds of Formula I can exist as one or more stereoisomers.
• the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
• geometric isomers in which R 2 of the i ino moiety may be syn or anti relative to B, or a mixture of syn and anti geometric isomers.
• one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and or to selectively prepare said stereoisomers.
• the compounds of Formula I may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
• Some compounds of Formula I can exist as one or more tautomers, and all tautomeric forms of such compounds are part of the present invention. Accordingly, the compounds of the invention may be present as a mixture of tautomers or the individual tautomers.
• the present invention comprises compounds selected from Formula I, N-oxides and salts thereof.
• nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair of electrons for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides.
• tertiary amines can form N-oxides.
• Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and -chloroperbenzoic acid (MCPB A), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane.
• peroxy acids such as peracetic and -chloroperbenzoic acid (MCPB A)
• hydrogen peroxide alkyl hydroperoxides
• alkyl hydroperoxides such as t-butyl hydroperoxide
• sodium perborate sodium perborate
• dioxiranes such as dimethydioxirane.
• the salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fomaric, lactic, aleic, alonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
• the salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic moiety such as a carboxylic acid or phenol.
• organic bases e.g., pyridine, ammonia, or triethylamine
• inorganic bases e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium
• J is a phenyl ring, a naphthyl ring system, a 5- or 6-membered heteroaromatic ring or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system wherein each ring or ring system is optionally substituted with 1 to 4 R 5 .
• phenyl optionally substituted with 1 to 4 R 5 is the ring illustrated as U-l in Exhibit 1, wherein R v is R 5 and r is an integer from 0 to 4.
• An example of a naphthyl group optionally substituted with 1 to 4 R 5 is illustrated as U-85 in Exhibit 1, wherein R v is R 5 and r is an integer from 0 to 4.
• Examples of 5- or 6-membered heteroaromatic rings optionally substituted with 1 to 4 R 5 include the rings U-2 through U-53 illustrated in Exhibit 1 wherein R v is R 5 and r is an integer from 0 to 4.
• J-l through J-5 below also denote 5- or 6-membered heteroaromatic rings.
• U-2 through U-20 are examples of J-l
• U-21 through U-35 and U-40 are examples of J-2
• U-36 through U-39 are examples of J-3
• U-41 through U-48 are examples of J-4 andU-49 through U-53 are examples of J-5.
• Examples of aromatic 8-, 9- or 10-membered fused heterobicyclic ring systems optionally substituted with 1 to 4 R 5 include U-54 through U-84 illustrated in Exhibit 1 wherein R v is R 5 and r is an integer from 0 to 4.
• G groups include those illustrated as G-l through G-41 in Exhibit 2 wherein m is an integer from 0 to 4.
• the term "optionally substituted" in connection with these G groups refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog.
• the G group can be attached to the remainder of Formula I through any available carbon or nitrogen of the G group by replacement of a hydrogen atom.
• the optional substituents can be attached to any available carbon or nitrogen by replacing a hydrogen atom.
• G comprises a ring selected from G-24 through G-29 and G-32 through G-35
• A is selected from O, S or NR 3 .
• G is G-3, G-5, G-7, G-9, G-16 through G-18, G- 23, and G-24 through G-29, and G-32 through G-35 (when A is NR 3 )
• the nitrogen atoms that require substitution to fill their valence are substituted with H or R 3 .
• R 1 and R 2 groups can be optionally substituted with one or more substituents.
• the term "optionally substituted” in connection with these groups refers to R 1 and/or R 2 groups that are unsubstituted or have at least one non-hydrogen substituent.
• optionally substituted R 1 and/or R 2 groups are those that are optionally substituted by replacement of a hydrogen on a carbon atom of the R 1 and/or R 2 group with one or more (up to the total number of hydrogens available for replacement in any specific R 1 and/or R 2 group) substituents independently selected from the substituents listed in the Summary of the Invention above. Although these substituents are listed, it is noted that they do not need to be present since they are optional substituents.
• R 1 and/or R 2 groups that are unsubstituted.
• each R 1 and R 2 can be independently (among others) Ci -Cg alkyl, C 2 -Cg alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, each optionally substituted with one or more substituents selected from (among others) a phenyl, phenoxy or 5- or 6-membered heteroaromatic ring, each ring optionally substituted with one to three substituents independently selected from R 6 .
• the term "optionally substituted” in connection with these groups refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog.
• substituents include the rings illustrated as U-l through U-53 and U-88 illustrated in Exhibit 1, except that such rings are optionally substituted with 1 to 3 substituents independently selected from R 6 rather than (R v ) r .
• R 6 substituents do not need to be present since they are optional substituents.
• each R 4 is independently (among others) a phenyl, benzyl, phenoxy or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted with one to three substituents independently selected from R 6 .
• R 4 groups refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog.
• R 4 groups include the rings illustrated as U- 1 through U-53, U-86 and U-88 illustrated in Exhibit 1, except that such rings are optionally substituted with 1 to 3 substituents independently selected from R 6 rather than ( ⁇ ) r . Note that R 6 substituents do not need to be present since they are optional substituents.
• each R 5 is independently (among others) a phenyl, benzyl, benzoyl, phenoxy, 5- or 6-membered heteroaromatic ring or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system, each ring or ring system optionally substituted with one to three substituents independently selected from R 6 .
• R 5 groups include the rings and ring systems illustrated as U-l through U-88 illustrated in Exhibit 1, except that such rings and ring systems are optionally substituted with 1 to 3 substituents independently selected from R 6 rather than (R v ) r . Note that R 6 substituents do not need to be present since they are optional substituents.
• R 2 is H; or Cj-Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, C ⁇ -C 2 alkoxy, C ⁇ -C 2 alkylthio, Ci-C 2 alkylsulfinyl and alkylsulfonyl; one R 4 group is attached to the phenyl ring at the 2-position or 5-position, and said R 4 is C r C 4 alkyl, C r C 4 haloalkyl, halogen, CN, NO 2 , C r C 4 alkoxy, C r C4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C j ⁇ alkylsulfonyl, Cj ⁇ haloalkylthi
• R 2 is C1-C4 alkyl optionally substituted with halogen, CN, OCH 3 or
• R 4 group is attached to the phenyl ring at the 2-position and said 4 is CH 3 , CF 3 , OCF 3 , OCHF 2 , S(O) p CF 3 , S(O) p CHF 2 , CN or halogen; a second R 4 is H, F, CI, Br, I.
• each R 5 is independently halogen, methyl, CF 3 , OCF 3 , OCHF 2 , S(O) p CF 3 , S(O) p CHF 2 , OCH 2 CF 3 , OCF 2 CHF 2 , S(O) p CH 2 CF 3 or S(O) p CF 2 CHF 2 ; or a phenyl, pyrazole, imidazole, triazole, pyridine or pyrimidine ring, each ring optionally substituted with one to three substituents independently selected from C1-C4 alkyl, C1-C 4 haloalkyl, halogen and CN; and p is 0, 1 or 2.
• Preferred 5 wherein R 2 is H, Me, Et, ⁇ -propyl or t-butyl.
• Preferred 6 Methods of Preferred 1 wherein
• J is a 5- or 6-membered heteroaromatic ring selected from the group consisting of J-l, J-2, J-3, J-4 and J-5, each J optionally substituted with 1 to 3 R 5
• Q is O, S, NH orNR 5 ;
• W, X, Y and Z are independently N, CH or CR 5 , provided that in J-4 and J-5 at least one of W, X, Y or Z is N.
• Preferred 7 Methods of Preferred 6 wherein B is O; and each R 5 is independently -C4 alkyl, C1-C4 haloalkyl, halogen, CN, NO 2 ,
• J substituted with 1 to 3 R 5 is selected from the group consisting of J-6, J-7, J-8, J-9, J-10, J-ll, J-12 and J-13
• V is N, CH, CF, CC1, CBr or CI; each R 6a is independently H or R 6 ;
• R 6 is C -C 6 alkyl, C 3 -C 6 cycloalkyl, C r C 6 haloalkyl, halogen, CN, C r C 4 alkoxy, C1-C4 haloalkoxy or C1-C4 haloalkylthio; eachR 7 is independently Cj-Cg alkyl, C ⁇ -C 6 haloalkyl, halogen, CN, C 1 -C4 alkoxy, C1-C 4 haloalkoxy or C ⁇ -C4 haloalkylthio; R 9 is C 2 -C 6 alkyl, C r C 6 haloalkyl, C 3 -C 6 alkenyl, C -C 6 haloalkenyl, C 3 -C 6 alkynyl or C3-C6 haloalkynyl; R l O is C r C 4 alkyl or C r C 4 haloalkyl;
• R 11 is C C alkyl; and n is 1 or 2.
• R 7 and R 9 are subsets of R 5 .
• the F, CI, Br or I atoms encompassed within V are a subset of R 6 .
• V is N.
• methods of Preferred 8 wherein V is CH, CF, CCl or CBr.
• methods of Preferred 8 wherein V is N or CH.
• R 2 is C1-C4 alkyl optionally substituted with halogen, CN, OCH 3 or S(O) p CH 3 ; or CH 2 C ⁇ CH; one R 4 group is attached to the phenyl ring at the 2-position and said R 4 is
• R 4 is H, F, CI, Br, I, CN or CF 3 ;
• R 6a is H, C1-C4 alkyl, C r C 4 haloalkyl, halogen or CN;
• R 7 is CH 3 , CF 3 , OCH 2 CF 3 , OCHF 2 or halogen;
• R 9 is CH 2 CF 3 , CHF 2 or CF 3 ; and p is 0, 1 or 2.
• methods of Preferred 9 wherein one R 4 group is attached to the phenyl ring at the 2- ⁇ osition and said R 4 is CH 3l CI or Br; and a second R 4 is H, F, CI, Br, I, CN or CF 3 .
• Methods of Preferred 9 wherein J substituted with 1 to 3 R 5 is J-6 ; V is N or CH; and R 7 is CH 3 , CF 3 , OCH 2 CF 3 , OCHF 2 or halogen.
• Methods of Preferred 10 wherein R 6a is F, CI or Br; and R 7 is halogen or
• V is N or CH; R 6a is CI or Br; and R 9 is CF 3 , CHF 2 , CH 2 CF 3 , CF 2 CHF 2 .
• R6a is CI or Br; and R 7 is CF 3 .
• Preferred 15 Methods of Preferred 9 wherein J substituted with from 1 to 3 R 5 is J-10;
• R 6a is CI or Br; and R 9 is CH 2 CF 3 , CHF 2 or CF 3 .
• Preferred 16 Methods of Preferred 9 wherein J substituted with from 1 to 3 R 5 is J-ll; R 6a is CI or Br; and R 7 is halogen, OCH 2 CF 3 , OCHF 2 or CF 3 .
• Methods of Preferred 9 wherein J substituted with from 1 to 3 R 5 is J-12; Rf ⁇ is CI or Br; R 7 is halogen, OCH 2 CF 3 , OCHF 2 or CF 3 ; and R 9 is CH 2 CF 3 , CHF 2 or CF 3 .
• Methods of Preferred 9 wherein J substituted with from 1 to 3 R 5 is J-13; R6. is CI or Br; and R 9 is CH 2 CF 3 , CHF 2 or CF 3 .
• Specifically preferred methods are those comprising compounds selected from the group consisting of: N-[2-[3-bromo- 1 -(3-chloro-2-pyridinyl)- lH-pyrazol-5-yl]-6-chloro-8-methyl-4H- 3 , 1 -benzoxazin-4-ylidene]methanamine, N-[2-[3-bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazol-5-yl]-6-chloro-8-methyl-4H-
• R 5 is J-6 (as defined above in Preferred 8); each R 1 is independently C ⁇ -Cg alkyl;
• compositions for controlling an invertebrate pest comprising a biologically effective amount of a compound of Formula I.
• Preferred compositions are those comprising the compounds described in Preferred 1 through Preferred 19 and those listed in the specifically preferred methods above.
• Preferred compounds for ease of synthesis and/or biological efficacy are: Preferred A. Compounds of Formula I wherein B is O;
• R 2 is ⁇ or Cj-Cg alkyl, C 2 -C alkenyl, C 2 -Cg alkynyl or C 3 -Cg cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, C ⁇ C 2 alkoxy, C ⁇ -C alkylthio, C 1 -C 2 alkylsulfinyl and C r C 2 alkylsulfonyl; one R 4 group is attached to the phenyl ring at the 2-position or 5-position, and said R 4 is C r C 4 alkyl, C r C 4 haloalkyl, halogen, CN, NO 2 , C r C 4 alkoxy, C ⁇ -0 haloalkoxy, C1-C 4 alkylthio, C 1 -C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C 4 haloal
• Preferred B Compounds of Preferred A wherein J is a phenyl group optionally substituted with from 1 to 4 R 5 ;
• R 2 is Cj -C4 alkyl optionally substituted with halogen, CN, OCH 3 or
• R 4 group is attached to the phenyl ring at the 2-position and said R 4 is
• a second R 4 is H, F, CI, Br, I or CF 3 ; each R 5 is independently halogen, methyl, CF 3 , OCF 3 , OCHF 2 , S(O) p CF 3 ,
• J is a 5- or 6-membered heteroaromatic ring selected from the group consisting of J-l, J-2, J-3, J-4 and J-5, each J optionally substituted with
• Q is O, S, NH orNR 5 ;
• W, X, Y and Z are independently N, CH or CR 5 , provided that in J-4 and J-5 at least one of W, X, Y or Z is N; and each R 5 is independently C r C4 alkyl, C ] ⁇ haloalkyl, halogen, CN, NO 2 , , Cj-04 haloalkoxy, ⁇ -C ⁇ alkylthio, C1-C4 alkylsulfinyl, C1-C 4 alkylsulfonyl, C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl, C r C 4 haloalkylsulfonyl or C 2 -C 4 alkoxycarbonyl; or a phenyl or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted with one to three substituents independently selected from R 6 .
• Preferred E Compounds of Preferred D
• V is N, CH, CF, CCl, CBr or CI; each R 6a is independently H or R 6 ;
• R 6 is C r C 6 alkyl, C 3 -C 6 cycloalkyl, C r C 6 haloalkyl, halogen, CN, C r C 4 alkoxy, C1-C4 haloalkoxy or C1-C4 haloalkylthio; each R 7 is independently C ⁇ Cg alkyl, C ⁇ -Cg haloalkyl, halogen, CN, C1-C4 alkoxy, C 1 -C4 haloalkoxy or C 1 -C 4 haloalkylthio; R 9 is C 2 -C 6 alkyl, C ⁇ -C 6 haloalkyl, C -C 6 alkenyl, C 3 -C 6 haloalkenyl, C -C 6 alkynyl or C 3 -C,5 haloalkynyl; R 10 is Cr-C-4 alkyl or C C 4 haloalkyl; R 11 is C 1 -C 4
• R 7 and R 9 are subsets of R 5 .
• the F, CI, Br or I atoms encompassed within V are a subset of R 6 .
• V is N.
• compounds of Preferred E wherein V is CH, CF, CCl or CBr.
• compounds of Preferred E wherein V is N or CH.
• Preferred F Compounds of Preferred E wherein
• R 2 is C1-C4 alkyl optionally substituted with halogen, CN, OCH 3 or
• R 4 is attached to the phenyl ring at the 2-position and said R 4 is CH 3 , CF 3 , OCF 3 , OCHF 2 , S(O) p CF 3 , S(O) p CHF 2 , CN or halogen;
• a second R 4 is H, F, CI, Br, I or CF 3 ;
• R 6a is H, C ⁇ -C-4 alkyl, C r C 4 haloalkyl, halogen or CN;
• R 7 is CH 3 , CF 3 , OCH 2 CF 3 , OCHF 2 or halogen;
• R 9 is CH 2 CF 3 , CHF 2 or CF 3 ; and p is 0, 1 or 2.
• R 4 is attached to the phenyl ring at the 2-position and said R 4 is CH 3 , CI or Br; and a second R 4 is H, F, CI, Br, I or CF .
• Preferred G Compounds of Preferred F wherein J substituted with from 1 to 3 R 5 is J-6; V is N or CH; and R 7 is CH 3 , CF 3 , OCH 2 CF 3 , OCHF 2 or halogen.
• Preferred H Compounds of Preferred G wherein R 6a is F, CI or Br; and R 7 is halogen or
• CF 3 Prefeired I. Compounds of Preferred F wherein J substituted with 1 to 3 R 5 is J-7; and R 9 is C 2 -C 6 alkyl or C r C 6 haloalkyl. Of note are compounds of Preferred I wherein V is N or CH; R 6a is CI or Br; and R 9 is CF 3 , CHF 2 , CH 2 CF 3 , CF 2 CHF 2 .
• R 6a is CI or Br
• R 7 is halogen or CF 3 .
• Preferred K Compounds of Preferred F wherein J substituted with 1 to 3 R 5 is J-9; R 6a is CI or Br; and R 7 is CF 3 .
• Preferred L Compounds of Preferred F wherein J substituted with 1 to 3 R 5 is J- 10; R 6a is CI or Br; and R 9 is CH 2 CF 3 , CHF 2 or CF 3 .
• Prefe ⁇ ed M Compounds of Preferred F wherein J substituted with 1 to 3 R 5 is J-l 1; R 6a is CI or Br; and R 7 is halogen, OCH 2 CF 3 , OCHF 2 or CF 3 .
• Prefe ⁇ ed N Compounds of Preferred F wherein J substituted with 1 to 3 R 5 is J-12; R 6a is CI or Br; R 7 is halogen, OCH 2 CF 3 , OCHF 2 or CF 3 ; and R 9 is CH 2 CF 3 , CHF 2 or CF 3 .
• Preferred O Compounds of Preferred F wherein J substituted with 1 to 3 R 5 is J-13; R 6a is CI or Br; and R 9 is CH 2 CF 3 , CHF 2 or CF 3 .
• Specifically preferred are compounds selected from the group consisting of: N-[2-[3-bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazol-5-yl]-6-chloro-8-methyl-4H-
• R 5 is J-6 (as defined above in Preferred 8); each R 1 is independently Ci -C alkyl; R 2 is ⁇ or C r C 6 alkyl; or
• Compounds of Formula la or lb can be prepared from compounds of Formula Ila or Formula JJb respectively by cyclization in the presence of dehydration agents such as POCl 3 , POCl 3 /PCl 5 , SOCl or oxalyl chloride.
• This cyclization is typically conducted in solvents such as dichloroethane, dichloromethane, chloroform, benzene, toluene, xylenes, hexanes, cyclohexane, 1,4-dioxane, tetrahydrofuran and chlorobenzene in the temperature range from 0 °C to the reflux temperature of the mixture.
• the dehydrative cyclization can be effected by treatment of Formula Ila or Formula ⁇ b with triphenyl phosphine and either bromine or iodine, optionally in the presence of tertiary arnine bases such as triethylamine or diisopropylethylamine. Se Monatsh. Chem. 1989, 120, 973-980 andJ. Org. Chem. 2000, 65, 1022-1030 for representative procedures.
• Coupling of an amine of Formula 2 with an acid chloride of Formula 3 in the presence of an acid scavenger can provide the compound of Formula Ila (Scheme 2).
• Typical acid scavengers include amine bases such as triethylamine, diisopropylethylamine and pyridine; other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate.
• polymer-supported acid scavengers such as polymer-bound diisopropylethylamine and polymer-bound dimethylaminopyridine.
• amides of Formula Ila can be converted to thioamides of Formula lib using a variety of standard thio transfer reagents including phosphorus pentasulfi.de and Lawesson's reagent.
• An alternate procedure for the preparation of compounds of Formula Ila involves coupling of an amine of Formula 2 with an acid of Formula 4 in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC), l, -carbonyldiimidazole, bis(2-oxo-3-oxazolidinyl)phosphinic chloride or benzotriazol-l-yloxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (Scheme 3).
• DCC dicyclohexylcarbodiimide
• l l
• -carbonyldiimidazole bis(2-oxo-3-oxazolidinyl)phosphinic chloride
• benzotriazol-l-yloxy-tris-(dimethylamino)- phosphonium hexafluorophosphate Scheme 3
• acid chlorides of Formula 3 may be prepared from acids of Formula 4 by numerous well-known methods.
• acid chlorides of Formula 3 are readily made from carboxylic acids of Formula 4 by reacting the carboxylic acid 4 with thionyl chloride or oxalyl chloride in an inert solvent such as toluene or dichloromethane in the presence of a catalytic amount of N,N-dimethylformamide.
• Amines of Formula 2 are typically available from the corresponding
• 2-nitrobenzamides of Formula 5 via catalytic hydrogenation of the nitro group (Scheme 4).
• Typical procedures involve reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon or platinum xide and in hydroxylic solvents such as ethanol and isopropanol. They can also be prepared by reduction with zinc in acetic acid. These procedures are well documented in the chemical literature.
• the intermediate 2-nitrobenzamides of Formula 5 are readily prepared from commercially available 2-nitrobenzoic acids (Scheme 5). Typical methods for amide formation can be applied here. These include direct dehydrative coupling of acids of Formula 6 with amines of Formula 7 using for example DCC, and conversion of the acids to activated forms such as the acid chlorides or anhydrides and subsequent coupling with amines to form amides of Formula 5. Alkyl chloroformates, such as ethyl chloroformate or isopropyl chloroformate, are especially useful reagents for this type of reaction involving activation of the acid. The chemical literature is extensive on methods for amide formation.
• Intermediate anthranilic amides of Formula 2 may also be prepared from isatoic anhydrides of Formula 8 as shown in Scheme 6.
• Typical procedures involve combination of equimolar amounts of the amine 7 with the isatoic anhydride in polar aprotic solvents such as pyridine and NN-dimethylformamide at temperatures ranging from room temperature to 100 °C.
• Isatoic anhydrides of Formula 8 may be made by methods described in Coppola, Synthesis 1980, 505-36.
• an alternate procedure for the preparation of compounds of Formula Ila involves reaction of an amine of Formula 7 with a benzoxazinone of Formula 10.
• the reaction of Scheme 7 can be run neat or in a variety of suitable solvents including tetrahydrofuran, diethyl ether, pyridine, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the reflux temperature of the solvent.
• suitable solvents including tetrahydrofuran, diethyl ether, pyridine, dichloromethane or chloroform
• benzoxazinones with amines to produce anthranilamides is well documented in the chemical literature.
• benzoxazinone chemistry see Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103 and references cited therein. See also Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.
• Benzoxazinones of Formula 10 can be prepared by a variety of procedures. Two procedures that are especially useful are detailed in Schemes 8 and 9.
• a benzoxazinone of Formula 10 is prepared directly via coupling of a carboxylic acid of Formula 4 with an anthranilic acid of Formula 11. This involves sequential addition of methanesulfonyl chloride to a carboxylic acid of Formula 4 in the presence of an amine base such as triethylamine or pyridine, followed by the addition of an anthranilic acid of Formula 11, followed by a second addition of triethylamine and methanesulfonyl chloride. This procedure generally affords good yields of the benzoxazinone and is especially useful for preparing compounds of Formula 10a from pyrazolecarboxylic acids of Formula 4a.
• Scheme 9 depicts an alternate preparation for benzoxazinones of Formulae 10 and 10a involving coupling of an acid chloride of Formula 3 with an isatoic anhydride of Formula 8 to provide the Formula 10 benzoxazinone directly.
• Compounds of Formula 10a can be prepared from the pyrazole acid chloride of Formula 3a by a similar procedure. Solvents such as pyridine or pyridine/acetonitrile are suitable for this reaction.
• the acid chlorides of Formula 3 a are available from the corresponding acids of Formula 4a by known procedures such as chlorination with thionyl chloride or oxalyl chloride.
• isatoic anhydrides of Formula 8 can be achieved from isatins of Formula 13 as outlined in Scheme 10. Isatins of Formula 13 are available from aniline derivatives of Formula 12 following literature procedures. Oxidation of isatin 13 with hydrogen peroxide generally affords good yields of the corresponding isatoic anhydride 8 (Angew. Chem. Int. Ed. Engl. 1980, 19, 222-223). Isatoic anhydrides are also available from the anthranilic acids 11 via many known procedures involving reaction of 11 with phosgene or a phosgene equivalent.
• Compounds of Formula Ic or Id can be prepared from anthranilonitriles of Formula 14 by cyclization with an amide of Formula 15 in the presence of dehydration agents such as POCl 3 , POCl 3 /PCl 5 or SOCl 2 (Scheme 11).
• This cyclization is typically conducted in solvents such as dichloroethane, dichloromethane, chloroform, benzene, toluene, xylenes, hexanes, cyclohexane, 1,4-dioxane, tetrahydrofuran and chlorobenzene in the temperature range from 0 °C to the reflux temperature of the mixture.
• the resultant compounds of Formula Ic (wherein R 2 is H) can be treated with electrophiles of Formula 16 (wherein Lg is a leaving group such as halogen and alkyl or aryl suphonates), optionally in the presence of an acid scavenger, to provide compounds of Formula Id (wherein R 2 is other than H).
• Typical acid scavengers include amine bases such as triethylamine, diisopropylethylamine and pyridine; other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate.
• polymer-supported acid scavengers such as polymer-bound diisopropylethylamine and polymer-bound dimethylaminopyridine.
• These reactions are typically conducted in solvents such as dichloroethane, dichloromethane, chloroform, benzene, toluene, xylenes, hexanes, cyclohexane, 1,4-dioxane, tetrahydrofuran dimethylsufoxide NN-dimethylformamide, NN-dimethylacetamide and chlorobenzene in the temperature range from 0 °C to the reflux temperature of the mixture.
• solvents such as dichloroethane, dichloromethane, chloroform, benzene, toluene, xylenes, hexanes, cyclohexane, 1,4-dioxane, tetrahydrofuran dimethylsufoxide NN-dimethylformamide,
• Compounds of Formula Id may be prepared from compounds of Foimulae 14 and 15 (wherein R 1 is H) by similar procedures. Alkylation of Formula Id with an alkylating agent with two leaving groups (e.g. ethylene dibromide or propylene dibromide) provides compounds of Formula Ie wherein, for example, the moiety R i -R 2 is CH 2 CH 2 or CH 2 CH 2 CH 2 . Scheme 11
• Lg is a Leaving group
• Lg is a Leaving group
• Amides of Formula 15 can be prepared from acids of Formula 4 or acid chlorides of Formula 3 by reaction with amines of the formula R NH 2 according to methods described for Schemes 2, 3 and 5.
• compounds of Formula If may also be prepared by the dehydration of compounds of Formula lie.
• Formula lie compounds can be prepared from anilines with an ⁇ rtzo-heterocycle containing a NH moiety (Formula 16) and compounds of Formula 3 in the presence of an acid scavenger according to methods described for Scheme 2.
• the dehydration of lie can occur under the coupling conditions to provide Formula If directly. See Example 3 for a more detailed example of this reaction sequence.
• Benzoic acids of Formula 4, wherein J is an optionally substituted phenyl ring are well known in the art and are commercially available or available by well-established procedures.
• Heterocyclic acids of Formula 4, wherein J is an optionally substituted heterocycle can be prepared by procedures outlined in Schemes 12-35.
• Heterocyclic acids particularly useful for preparing compounds of Formula I of this invention include pyridine acids, pyrimidine acids and pyrazole acids. Procedures for the synthesis of representative examples of each are detailed in Schemes 12-35. A variety of heterocyclic acids and general methods for their synthesis may be found in PCT Patent Application Publication WO 98/57397.
• Synthesis of pyrazoles of Formula 4a is also described in Scheme 13. These acids may be prepared via metallation and carboxylation of compounds of Formula 20 as the key step.
• the R 5a group is introduced in a manner similar to that of Scheme 12, i.e. via alkylation or arylation with a compound of Formula 18.
• Representative R 5 groups include e.g. cyano, haloalkyl and halogen.
• pyrazoles of Formula 4c are described in Scheme 15. They can be prepared via reaction of an optionally substituted phenyl hydrazine of Formula 21 with a ketopyruvate of Formula 22 to yield pyrazole esters of Formula 23. Hydrolysis of the esters affords the pyrazole acids of Formula 4c. This procedure is particularly useful for the preparation of compounds in which R 5a is optionally substituted phenyl and R 5b is haloalkyl.
• the starting pyrazoles of Formula 19 are known compounds or can be prepared according to known methods.
• the pyrazole of Formula 19a (the compound of Formula 19 wherein R 5 is CF 3 and R 5c is H) is commercially available.
• the pyrazoles of Formula 19c (compounds of Formula 19 wherein R 5 is CI or Br and R 5c is H) can be prepared by literature procedures (Chem. Ber. 1966, 99(10), 3350-7). A useful alternative method for the preparation of compound 19c is depicted in Scheme 17.
• Reaction of the dimethylaminoylidene ketoester of Formula 45 with hydrazine affords the pyrazole of Formula 50.
• Reaction of the pyrazole 50 with an alkylating agent of Formula 51 affords a mixture of pyrazoles of Formulae 52 and 53.
• This mixture of pyrazole isomers is readily separated by chromatographic methods and converted to the corresponding acids 4h and 4f, respectively.
• Preferred R 5d substituents include alkyl and haloalkyl groups.
• a general synthesis of pyrrole acids of Formula 4j is depicted in Scheme 24.
• Treatment of a compound of Formula 58 with 2,5-dimethoxytetrahydrofuran (59) affords a pyrrole of Formula 60.
• Formylation of the pyrrole 60 to provide the aldehyde of Formula 61 can be accomplished by using standard Nilsmeier-Haack formylation conditions, such as treatment with N,N-dimethylformamide (DMF) and phosphorus oxychloride.
• Halogenation of the compound of Formula 61 with N-halosuccinimides ( ⁇ XS) such as N-chlorosuccmimide or N-bromosuccinimide occurs preferentially at the 4-position of the pyrrole ring.
• Oxidation of the halogenated aldehyde affords the pyrrole acid of Formula 4j .
• the oxidation can be accomplished by using a variety of standard oxidation conditions.
• Pyrazolecarboxylic acids of Formula 4q wherein R 7 is CF 3 can be prepared by the method outlined in Scheme 30.
• the suitable base can be, for example but not limitation, sodium hydride, potassium t-butoxide, dimsyl sodium (CH 3 S(O)CH ⁇ Na + ), alkali metal (such as lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl (such as methyl, ethyl or butyl)ammonium fluorides or hydroxides, or2-tert-buty_limmo-2-diethylam o-l,3-dimethyl- perhydro-l,3,2-&a2aphosphonine.
• a suitable base can be, for example but not limitation, sodium hydride, potassium t-butoxide, dimsyl sodium (CH 3 S(O)CH ⁇ Na + ), alkali metal (such as lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl (such as methyl, ethyl or butyl)ammonium fluorides or hydroxides, or2-tert-buty_limm
• the suitable organic solvent can be, for example but not limitation, acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylsulfoxide, or N,N-dimethylformamide.
• the cyclization reaction is usually conducted in a temperature range from about 0 to 120 °C.
• the effects of solvent, base, temperature and addition time are all interdependent, and choice of reaction conditions is important to minimize the formation of byproducts .
• a preferred bas e is tetrabutylammonium fluoride.
• the dehydration is effected by treatment with a catalytic amount of a suitable acid.
• This catalytic acid can be, for example but not limitation, sulfuric acid.
• the reaction is generally conducted using an organic solvent.
• dehydration reactions may be conducted in a wide variety of solvents in a temperature range generally between about 0 and 200 °C, more preferably between about 0 and 100 °C).
• a solvent comprising acetic acid and temperatures of about 65 °C are preferred.
• Carboxylic ester compounds can be converted to carboxylic acid compounds by numerous methods including nucleophilic cleavage under anhydrous conditions or hydrolytic methods involving the use of either acids or bases (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 for areview of methods).
• bases include alkali metal (such as lithium, sodium or potassium) hydroxides.
• the ester can be dissolved in a mixture of water and an alcohol such as ethanol.
• the ester Upon treatment with sodium hydroxide or potassium hydroxide, the ester is saponified to provide the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, yields the carboxylic acid of Formula 4q.
• the carboxylic acid can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.
• Hydrazine compounds of Formula 84 can be prepared by standard methods, such as by contacting the corresponding halo compound of Formula 18a (Scheme 14) with hydrazine.
• Pyrazolecarboxylic acids of Formula 4r wherein R 7 is CI or Br can be prepared by the method outlined in Scheme 32.
• Oxidization of the compound of Formula 88 optionally in the presence of acid to give the compound of Formula 89 followed by conversion of the carboxylic ester function to the carboxylic acid provides the compound of Formula 4r.
• the oxidizing agent can be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®) or potassium permanganate.
• at least one equivalent of oxidizing agent versus the compound of Formula 88 should be used, preferably between about one to two equivalents. This oxidation is typically carried out in the presence of a solvent.
• the solvent can be an ether, such as tetrahydrofuran, j ⁇ -dioxane and the like, an organic ester, such as ethyl acetate, dimethyl carbonate and the like, or a polar aprotic organic such as N,N-dimethylformamide, acetonitrile and the like.
• Acids suitable for use in the oxidation step include inorganic acids, such as sulfuric acid, phosphoric acid and the like, and organic acids, such as acetic acid, benzoic acid and the like.
• the acid, when used, should be used in greater than 0.1 equivalents versus the compound of Formula 88. To obtain complete conversion, one to five equivalents of acid can be used.
• the preferred oxidant is potassium persulfate and the oxidation is preferably carried out in the presence of sulfuric acid.
• the reaction can be carried out by mixing the compound of Formula 88 in the desired solvent and, if used, the acid. The oxidant can then be added at a convenient rate.
• the reaction temperature is typically varied from as low as about 0 °C up to the boiling point of the solvent in order to obtain a reasonable reaction time to complete the reaction, preferably less than 8 hours.
• the desired product, a compound of Formula 89 can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation. Methods suitable for converting the ester of Formula 89 to the carboxylic acid of Formula 4r are already described for Scheme 30.
• Compounds of Formula 88 can be prepared from corresponding compounds of
• Halogenating reagents that can be used include phosphorus oxyhahdes, phosphonis trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphophoranes, dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred are phosphorus oxyhahdes and phosphorus pentahalides.
• At least 0.33 equivalents of phosphorus oxyhalide versus the compound of Formula 90 should be used, preferably between about 0.33 and 1.2 equivalents.
• at least 0.20 equivalents of phosphorus pentahalide versus the compound of Formula 90 should be used, preferably between about 0.20 and 1.0 equivalents.
• Compounds of Formula 90 wherein R 12 is C1-C4 alkyl are preferred for this reaction.
• Typical solvents for this halogenation include halogenated alkanes, such as dichloromethane, chloroform, chlorobutane and the like, aromatic solvents, such as benzene, xylene, chlorobenzene and the like, ethers, such as tetrahydrofuran, -dioxane, diethyl ether, and the like, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, and the like.
• an organic base such as triethylamine, pyridine, N,N-dimethylaniline or the like, can be added.
• Addition of a catalyst is also an option.
• Preferred is the process in which the solvent is acetonitrile and a base is absent. Typically, neither a base nor a catalyst is required when acetonitrile solvent is used.
• the preferred process is conducted by mixing the compound of Formula 90 in acetonitrile. The halogenating reagent is then added over a convenient time, and the mixture is then held at the desired temperature until the reaction is complete.
• the reaction temperature is typically between 20 °C and the boiling point of acetonitrile, and the reaction time is typically less than two hours.
• reaction mass is then neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide and the like, or an organic base, such as sodium acetate.
• an inorganic base such as sodium bicarbonate, sodium hydroxide and the like
• organic base such as sodium acetate.
• the desired product, a compound of Formula 88 can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.
• compounds of Formula 88 wherein R 7 is Br or CI can be prepared by treating the corresponding compounds of Formula 88 wherein R 7 is a different halogen (e.g., CI for making Formula 88 wherein R 7 is Br) or a sulfonate group such as 7-toluenesulfonate with hydrogen bromide or hydrogen chloride, respectively.
• a halogen e.g., CI for making Formula 88 wherein R 7 is Br
• a sulfonate group such as 7-toluenesulfonate with hydrogen bromide or hydrogen chloride, respectively.
• the R 7 halogen or sulfonate substituent on the Formula 88 starting compound is replaced with Br or CI from hydrogen bromide or hydrogen chloride, respectively.
• the reaction is conducted in a suitable solvent such as dibromomethane, dichloromethane or acetonitrile.
• the reaction can be conducted at or near atmospheric pressure or above atmospheric pressure in a pressure vessel
• R 7 in the starting compound of Formula 88 is a halogen such as CI
• the reaction is preferably conducted in such a way that the hydrogen halide generated from the reaction is removed by sparging or other suitable means.
• the reaction can be conducted between about 0 and 100 °C, most conveniently near ambient temperature (e.g., about 10 to 40 °C), and more preferably between about 20 and 30 °C.
• Addition of a Lewis acid catalyst such as aluminum tribromide for prepaiing Formula 88 wherein R 7 is Br
• the product of Formula 88 is isolated by the usual methods known to those skilled in the art, including extraction, distillation and crystallization.
• Starting compounds of Formula 88 wherein R 7 is CI or Br can be prepared from corresponding compounds of Formula 90 as already described.
• Starting compounds of Formula 88 wherein R 7 is a sulfonate group can likewise be prepared from corresponding compounds of Formula 90 by standard methods such as treatment with a sulfonyl chloride (e.g., / toluenesulfonyl chloride) and base such as a tertiary amine (e.g., triethylamine) in a suitable solvent such as dichloromethane.
• a sulfonyl chloride e.g., / toluenesulfonyl chloride
• base such as a tertiary amine (e.g., triethylamine) in a suitable solvent such as dichloromethane.
• the compound of Formula 91 is then alkylated to form the compound of Formula 93 (R 7 is OCH 2 CF 3 ) by contact with an alkylating agent CF 3 CH 2 Lg (92) in the presence of a base.
• Lg is a nucleophilic reaction leaving group such as halogen (e.g., Br, I), OS(O) 2 CH 3 (methanesulfonate), OS(O) 2 CF 3 , OS(O) 2 Ph- ⁇ -CH 3 (jc-toluenesulfonate), and the like; methanesulfonate works well.
• the reaction is conducted in the presence of at least one equivalent of a base.
• Suitable bases include inorganic bases, such as alkali metal (such as hthium, sodium or potassium) carbonates and hydroxides, and organic bases, such as triethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]- undec-7-ene.
• alkali metal such as hthium, sodium or potassium
• organic bases such as triethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]- undec-7-ene.
• the reaction is generally conducted in a solvent, which can comprise alcohols, such as methanol and ethanol, halogenated alkanes, such as dichloromethane, aromatic solvents, such as benzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, and polar aprotic solvents, such as acetonitrile, N,N-dimethylformamide, and the like. Alcohols and polar aprotic solvents are preferred for use with inorganic bases. Potassium carbonate as base and acetonitrile as solvent are preferred.
• the reaction is generally conducted between about 0 and 150 °C, with most typically between ambient temperature and 100 °C.
• R 13 is H conversion ⁇ 4t R 13 is H wherein R* 2 is C1-C4 alkyl, and Lg is a leaving group.
• the compound of Formula 91 can also be alkylated to form the compound of Formula 95 (R 7 is OCHF 2 ) by contact with difluorocarbene, prepared from CHC1F 2 in the presence of a base.
• the reaction is generally conducted in a solvent, which can comprise ethers, such as tetrahydrofuran or dioxane, and polar aprotic solvents, such as acetonitrile, N 5 N-dimethylformamide, and the like.
• the base can be selected from inorganic bases such as potassium carbonate, sodium hydroxide or sodium hydride.
• the reaction is conducted using potassium carbonate with N,N-dimethylformamide as the solvent.
• the esters of Formula 93 or 95 can be isolated by conventional techniques such as extraction. The esters can then be converted to the carboxylic acids of Formula 4 or 4t by the methods already described for the conversion of Formula 83 to Formula 4q in Scheme 30. As outlined in Scheme 35, compounds of Formula 90 can be prepared from compounds of Formula 84 (see Scheme 31).
• R 12 is C1-C4 alkyl.
• a hydrazine compound of Formula 84 is contacted with a compound of Formula 96 (a fumarate ester or aleate ester or a mixture thereof may be used) in the presence of a base and a solvent.
• the base is typically a metal alkoxide salt, such as sodium ethoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, hthium tert-butoxide, and the like.
• Greater than 0.5 equivalents of base versus the compound of Formula 84 should be used, preferably between 0.9 and 1.3 equivalents.
• Greater than 1.0 equivalents of the compound of Formula 96 should be used, preferably between 1.0 to 1.3 equivalents .
• Polar protic and polar aprotic organic solvents can be used, such as alcohols, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and the like.
• Preferred solvents are alcohols such as methanol and ethanol. It is especially preferred that the alcohol be the same as that making up the fumarate or maleate ester and the alkoxide base.
• the reaction is typically conducted by mixing the compound of Formula 84 and the base in the solvent. The mixture can be heated or cooled to a desired temperature and the compound of Formula 96 added over a period of time. Typically reaction temperatures are between 0 °C and the boiling point of the solvent used.
• the reaction may be conducted under greater than atmospheric pressure in order to increase the boiling point of the solvent. Temperatures between about 30 and 90 °C are generally preferred.
• the addition time can be as quick as heat transfer allows. Typical addition times are between 1 minute and 2 hours. Optimum reaction temperature and addition time vary depending upon the identities of the compounds of Formula 84 and Formula 96.
• the reaction mixture can be held for a time at the reaction temperature. Depending upon the reaction temperature, the required hold time may be from 0 to 2 hours. Typical hold times are 10 to 60 minutes.
• the reaction mass then can be acidified by adding an organic acid, such as acetic acid and the like, or an inorganic acid, such as hydrochloric acid, sulfuric acid and the like.
• the -CO 2 R 12 function on the compound of Formula 90 may be hydrolyzed to -CO 2 H; for example, the presence of water in the reaction mixture can promote such hydrolysis. If the carboxylic acid (-CO 2 H) is formed, it can be converted back to -CO R 12 wherein R 12 is C J-C4 alkyl using esterification methods well known in the art.
• the desired product, a compound of Formula 90 can be isolated by methods known to those skilled in the art, such as crystallization, extraction or distillation.
• Step B Preparation of 1 -(3-chloiO-2-pyridinyl)-3-(trifluoromethyl)- lH-pyrazole-5- carboxylic acid
• a solution of the pyrazole product from Step A (105.0 g, 425 mmol) in dry tetrahydrofuran (700 mL) at -75 °C was added via cannula a -30 °C solution of lithium diisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL).
• the deep red solution was stirred for 15 minutes, after which time carbon dioxide was bubbled through at -63 °C until the solution became pale yellow and the exothermicity ceased.
• the reaction was stirred for an additional 20 minutes and then quenched with water (20 mL).
• the solvent was removed under reduced pressure, and the reaction mixture partitioned between ether and 0.5 ⁇ aqueous sodium hydroxide solution.
• the aqueous extracts were washed with ether (3x), filtered through Celite® diatomaceous filter aid to remove residual solids, and then acidified to a p ⁇ of approximately 4, at which point an orange oil formed.
• the aqueous mixture was stmed vigorously and additional acid was added to lower the p ⁇ to 2.5-3.
• Step D Preparation of l-(3-chloro-2-pyridinyl)-N-[2-methyl-6-r[(l- methyletiiyl)ammo]carbonyl1phenyl1-3-(trifluoromethyl)-lH-pyrazole-5- carboxamide
• NN-dimethylformamide 12 drops
• oxalyl chloride 15.8 g, 124 mmol
• the reaction mixture was stirred at room temperature until gas evolution ceased (approximately 1.5 hours).
• the reaction mixture was concentrated in vacuo to provide the crude acid chloride as an oil that was used without further purification.
• the crude acid chloride was dissolved in acetonitrile (95 mL) and added to a solution of the benzoxazin-2,4-dione prepared as in Step C in acetonitrile (95 mL).
• the resulting mixture was stirred at room temperature (approximately 30 minutes). Pyridine (95 mL) was added and the mixture heated to about 90 °C (approximately 1 hour).
• the reaction mixture was cooled to about 35 °C and isopropylamine (25 mL) was added.
• the reaction mixture exothermically warmed during the addition and then was maintained at about 50 °C
• Step E Preparation of N-[2- l- 3-chloiO-2-pwidinylV3-(trifluoromethylVlH-pyrazol-
• Step B Preparation of l- 2-chlorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5- carboxylic acid
• acetonitrile 400 mL
• ⁇ a ⁇ 2 PO 4 120 g, 0.87 mole
• Sodium hypochlorite solution 5.25% in water, 128 g, 2.6 mole
• the orange solution was maintained at room temperature for 30 minutes.
• reaction mixture was cooled in an ice bath and a solution of NaClO 2 in 560 mL of water was added dropwise, keeping the temperature below 11 °C. Gas evolution was observed and an aqueous sodium hydroxide scrubber was used to quench evolved chlorine. After the addition was complete, the reaction mixture was kept cold for one hour then allowed to reach room temperature overnight. To the reaction mixture was added 80 mL of concentrated hydrochloric acid dropwise to bring the pH below 3. The reaction mixture was extracted twice with ethyl acetate and the combined organic extracts were added dropwise rapidly with stirring to a cooled ( ⁇ 15 °C) solution of 300 g of NAHSO 3 in 1300 mL of water.
• Step C Preparation of l-(2-chlorophenyl)-3-(trifluoromethyl -lH- ⁇ yrazole-5- carbonyl chloride
• methylene chloride 300 mL
• the solution was treated with oxalyl chloride (15.7 mL, 0.18 mole), followed by N,N-dimethylformamide (12 drops). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst.
• Step D Preparation of l-(2-chlorophenyl)-N-[2-methyl-6-[fYl- methylethyl) am inn] carbonyllphenyl] -3 -ftrifluoromethyl)- 1 ⁇ -pyrazole-5- ' carboxamide
• Step C To a sample of the title compound of Example 1, Step C (22.3 g, 0.126 mole), suspended in acetonitrile (100 mL) was added crude l-(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazole-5-carbonyl chloride (43 g). The mixture was diluted with 350 mL of pyridine and heated to approximately 95 °C for a period of 2 hours. The mixture was cooled to 29 °C, then was treated with isopropylamine (32.2 mL, 0.38 mole). The reaction mass self- heated to 60 °C and was maintained at about 50 °C for one hour, then stirred overnight. The reaction mixture was poured into 1 L of water and stirred.
• the resulting solid was collected by filtration and washed with water.
• the wet cake was taken up in a mixture of dichloromethane and methanol, the water removed, and the organic phase was dried with molecular sieves and filtered. Nolatiles were removed on a rotary evaporator.
• the crude product was triturated with 1 : 1 ether/hexane, collected by filtration and washed with hexanes to yield 42.6 g of a light tan solid melting at 230-231 °C.
• Step E Prepa ⁇ -atio ofN- 2-[l-r2-chloro ⁇ henylV3- trifluoromethyl -lH-pyrazol-5- yll-8-methyl-4H-3.1-benzoxazin-4-ylidene]-2-propanamine
• 5 mL of thionyl chloride was added and the solution heated at reflux for 8 hours.
• the solvent was removed in vacuo and remaining residue partitioned between 70 mL of ethyl acetate and water.
• the organic layer was separated, washed with water, saturated aqueous sodium bicarbonate and brine.
• Step B Preparation of 7.9-Dichloro-5-[ 1 -(3-chloro-2-pyridinyl)-3-(trifluoromethyll- lH-pyrazol-5-yl]-2.3-dihydroimidazo[1.2-c3quinazoline
• Example 3 Isolation of the first-eluting material gave the title compound of Example 3, a compound of the invention, as a yellow solid (62 mg).
• a second-eluting material (31 mg) was l-(3-CMoro-2-pvridmyl)-N-[2,4-dicUoro-6-(4,5-dhydro-lH-imidazol- 2-yl)phenyl]-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide, the precursor to Example 3.
• R 5b is CF 3
• R 5b is OCF 3
• R 5b is CF(CF 3 ⁇ 2 2
• R 4a s R5a RE
• R 5b is CF 3
• R 5b is CF(CF 3 ⁇ 2 s2 E*!
• R4b R 5a R5a S2
• R4a R4b R5a z ' -Pr Me H Me Me Me z ' -Pr Me H Me t-Pr CI H Me Me Me z ' -Pr Me CI Me Me z'-Pr Me CI Me Me Me z'-Pr Me CI Me Me Me z'-Pr Me CI Me Me Me z'-Pr Me CI Me Me Me z'-Pr Me CI Me Me Me z ' -Pr Me CI Me z-Pr Me Br Me Me Me z'-Pr Me Br Me Me Me t-Pr CI Br Me Me Me z'-Pr CI Br Me t-Bu Me CI Br Me Me t-Bu Me Br Me Me t-Bu Me Br Me Me Me z'-Pr CI Br Me t-Bu
• R 5b is CF 3
• R 5 is OCF
• R 5b is CF(CF 3 ) 2
• R 5b is CF 3
• R 5b is OCF 3
• R 5b is CF(CF 3 ) 2

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